In this study of regional Cerebral Blood Flow (rCBF) in normal aging and Alzheimer's disease (AD), results to date indicate that: 1) AD is associated with substantial reductions of mean cortical perfusion, compared to normal aging, 2) these flow reductions are greatest in a parietotemporal focus, and minimal in periRolandic and occipital regions, 3) the distinct regional flow pattern of AD can achieve highly effective discrimination of such patients from normal aging and other diseases, and thus may be diagnostically useful, and 4) these rCBF abnormalities, although related to age- at-onset (AAO) and severity, are largely present in all patients, and do not lose sensitivity even at very early stages of the disease. Consequently, the current proposal is intended to complete documentation of rCBF as a diagnostic marker, test the validity if its discrimination in a new patient sample, continue longitudinal follow-up of current cohorts, and begin to develop a cohort of high-risk individuals to assess the possibility of predictive discrimination. The current samples of 60 AD patients and 60 normal controls will be recruited and entered, and longitudinally followed. A new sample of 32 patients will be recruited at another hospital, independently diagnosed by another group. Finally, 200 first- degree relatives of AD probands will be recruited and followed as a high-risk sample. All subjects will undergo diagnostic procedures, a short neuropsychological battery, and rCBF measurements at rest and during cognitive challenge. All AD patients will be rigorously stratified by AAO, crossed with severity of disease. For assignment to severity groups, it is required that each patient show-concordant scores on three dimensions: duration of disease, cognitive deficits, and activities of daily living. This design will provide a test of rCBF discrimination between AD patients and elderly controls, as well as discrimination among the four subsamples stratified by AAO and severity. Additionally, family members will provide data on the temporal relations between rCBF changes and eventual symptomatic manifestations and AD diagnosis. Finally, the assessment of rCBF response to cognitive challenge may provide insights into the mechanisms of disease, and may have implications for selection of patients in therapeutic trials.